Pyrrolo (2.1a)dihydroisoquinolines and their use as phosphodiesterase 10a inhibitors

ABSTRACT

The present invention relates to pyrrolo[2.1-a]dihydroisoquinolines which are inhibitors of phosphodiesterase 10a and can be used for combating cancer.

This application is a 371 of PCT/EP01/14187, filed Dec. 4, 2001.

The present invention relates to pyrrolo[2.1-a]dihydroisoquinolineswhich are inhibitors of phosphodiesterase 10a, a process for preparingthose compounds and a method of treating cancer by administering thosecompounds.

Cyclic AMP metabolism is regulated by the opposing activities ofadenylyl cyclase, which generates cAMP in response to extracellularstimuli (e.g. engagement of G-protein coupled receptors by their cognateligands), and 3′,5′-cyclic nucleotide phosphodiesterases (PDEs), whichhydrolyze cAMP to 5′-AMP. Signal transduction via cAMP is associatedwith transcriptional events that can result in the inhibition ofcellular proliferation (W. L. Lowe et al., Endocrinology 138, 2219(1997); D. A. Albert, J. Clin. Invest. 95, 1490 (1995); M. I. Medniekset al., FEBS Lett. 254, 83 (1989)). Indeed, elevation of intracellularcAMP concentration is growth inhibitory for several human tumor celllines, including those derived from breast, lung and colorectalcarcinomas (I. S. Fentimen et al., Mol. Biol. Med. 2, 81 (1984); P.Cassoni et al., Int. J. Cancer 72, 340 (1997); H. Shulamith et al.,Biochem. Pharmacol. 56, 1229 (1998); N. M. Hoosein et al., Regul.Peptides 24, 15 (1989)). In several human breast carcinoma cell lines,increased cAMP production through stimulation of adenylate cyclaseactivity and/or reduction in cAMP catabolism through inhibition ofphosphodiesterase activity has been shown to result in increased steadystate levels of cAMP and growth inhibition (N. Veber et al., Eur. J.Cancer 30A, 1352 (1994); J. A. Fontana et al., J. Natl. Cancer Inst. 78,1107 (1987); T. A. Slotkin et al., Breast Cancer Res. and Treatment 60,153 (2000)). In contrast to breast tumor cell lines, normal humanmammary epithelial cells are stimulated to proliferate by elevation ofintracellular cAMP (I. S. Fentimen et al., Mol. Biol. Med. 2, 81(1984)). These observations suggest that elevation of intracellular cAMPmay selectively inhibit breast tumor cell proliferation. Interestingly,it has been reported that neoplastic mammary tissues have higher levelsof low-Km phosphodiesterase activity compared to normal breast tissue,suggesting that tumors may gain a growth or survival advantage bykeeping intracellular cAMP levels in check (A. Larks Singer et al.,Cancer Res. 36, 60 (1976)).

The ICAST (inhibitor of Cyclic AMP Signal Transduction) gene encodes aspecific 3′,5′-cyclic nucleotide phosphodiesterase. Compared tocorresponding normal tissues, ICAST mRNA is overexpressed in breastcarcinoma specimens, liver metastases of colorectal carcinoma andnon-small cell lung carcinomas. The ICAST cDNA was also recently clonedby other groups and named PDE 10a (K. Fujishige et al., J. Biol. Chem.274, 18 438 (1999); S. H. Soderling et al., Proc. Natl. Acad. Sci. USA96, 7071 (1999); K. Loughey et al., Gene 234, 109 (1999)). Publishedexpression data for ICAST mRNA show a very limited distribution acrossadult human tissues, with highest levels observed in the testis, caudatenucleus and putamen (K. Fujishige et al., 1999). Increased expression ofICAST mRNA in human tumor specimens indicates that ICAST may play animportant role in tumor cell growth and/or survival under conditions ofelevated cAMP generation. Selective inhibition of ICAST activity intumor cells should lead to increased cAMP concentrations and growthinhibition. The expression profile of ICAST and the published reportsindicating that breast, lung and colon carcinomas are particularlysensitive to elevation of intracellular cAMP indicate that ICAST mayplay critical roles specifically in those tumor types. In addition toelevation of cAMP, inhibition of ICAST activity should also decrease theintracellular concentration of 5-AMP, which could limit purine pools andDNA synthesis in rapidly dividing tumor cells.

Certain pyrrolo[2.1-a]isoquinoline derivatives are known from theliterature as, for example, hypotensive agents or psychotropic agents(e.g. GB-A 1,153,670; U.S. Pat. No. 4,694,085; Meyer, Liebigs Ann. Chem.9, 1534-1544 (1981)). Pyrrolo[2.1-a]isoquinoline derivatives for thetreatment of dermatologic diseases such as psoriasis are disclosed in WO98/55118. However, the compounds disclosed in WO 98/55118 are describedas having virtually no cytotoxic activity.

Pyrrolo[2.1-a]isoquinoline derivatives of formula (A) are described inJ. Med. Chem. 27, 1321 (1984) and in J. Med. Chem. 31, 2097 (1988):

-   -   R′=H, OMe, Cl    -   R″=H, Cl    -   R″′=H, Me    -   R″″, R″″′=Me, Et, i-Pr, C₆H₁₁

These compounds are described as having antineoplastic activity, whichhowever is stated to be due to the carbamate moieties beingelectrophilic centers enabling the compounds (A) to react via analkyl-oxygen cleavage mechanism. It is not mentioned that thesecompounds have any PDE 10a inhibitory activity.

Tetracyclic compounds of formula (B) containing apyrrolo[2.1-a]isoquinoline moiety are described in Arch. Pharm. 321, 481(1988):

-   -   R=H, OMe

The compounds (B) are described as having anti-tumor activity due totheir ability to intercalate into DNA. It is not mentioned that thesecompounds have any PDE 10a inhibitory activity.

Surprisingly, it has been found that thepyrrolo[2.1-a]dihydroisoquinolines of the present invention inhibit PDE10a and exhibit an antiproliferative activity.

The present invention relates to compounds of the formula

-   -   wherein

-   x and y independently from each other denote zero or 1 with the    proviso that x+y=1 or 2;

-   R¹ and R² independently from each other denote hydrogen, C₁₋₄-alkyl    or CF₃ or

-   R¹ and R² together form a C₁₋₄-alkylene bridge;

-   R³ and R⁴ independently from each other denote C₁₋₄-alkyl;

-   R⁵ denotes C₆₋₁₄-aryl, optionally having 1 to 3 further substituents    selected from the group consisting of    -   halogen;    -   C₁₋₆-alkyl which can be further substituted with one or more        radicals selected from the group consisting of OH, halogen, NH₂        and C₁₋₆-alkoxy;    -   C₁₋₆-alkoxy which can be further substituted with one or more        radicals selected from the group consisting of OH, halogen, NH₂,        C₁₋₆-alkoxy and C₆₋₁₀-aryloxy;    -   OH;    -   NO₂;    -   CN;    -   CF₃;    -   OCF₃;    -   NR⁶R⁷;    -   SR⁸;    -   —O—(CH₂)₁₋₄—O— wherein the oxygen atoms are bound to the aryl        moiety in or-tho-position to each other;    -   phenyloxy or benzyloxy wherein the phenyl moieties optionally        contain one further substituent selected from the group        consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, and NO₂;    -   phenyl, optionally substituted with CN; and    -   4- to 9-membered aromatic heterocyclyl containing 1 to 4 hetero        atoms selected from the group consisting of N, O, and S;

-   R⁶ and R⁷ independently from each other denote hydrogen, C₁₋₆-alkyl    or, together with the nitrogen atom to which they are attached, form    a 5- to 7-membered saturated, partially unsaturated or aromatic ring    which can contain up to 3 further hetero atoms selected from the    group consisting of N, O, and S, and which ring can contain 1 to 3    substituents selected from the group consisting of C₁₋₆-alkyl,    C₁₋₆-alkoxy, C₆₋₁₀-aryl, and 4 to 9-membered aromatic heterocyclyl    containing 1 to 4 hetero atoms selected from the group consisting of    N, O, and S; and

-   R⁸ denotes hydrogen, C₁₋₆-alkyl or C₆₋₁₀-aryl-C₁₋₆-alkyl

-   with the proviso that    8,9-dimethoxy-3-methyl-2-phenyl-5,6-dihydro-pyrrolo-[2.1-a]-isoquinoline-1-carboxylic    acid ethyl ester is excluded,

-   and an isomer, a pharmaceutically acceptable) salt, a hydrate or a    hydrate of a (pharmaceutically acceptable) salt thereof.

An alternative embodiment of the present invention relates to compoundsof formula (I), wherein

-   x and y independently from each other denote zero or 1 with the    proviso that x+y=1 or 2;-   R¹ and R² independently from each other denote hydrogen, C₁₋₄-alkyl    or CF₃ or-   R¹ and R² together form a C₁₋₄-alkylene bridge;-   R³ and R⁴ independently from each other denote C₁₋₄-alkyl;-   R⁵ denote (i) phenyl, optionally having 1 to 3 further substituents    selected from the group consisting of    -   F, Cl, Br;    -   C₁₋₆-alkyl;    -   C₁₋₆-alkoxy;    -   C₆₋₁₀-aryloxy-C₁₋₆-alkoxy;    -   OH;    -   NO₂;    -   CN;    -   CF₃;    -   OCF₃;    -   NR⁶R⁷;    -   SR⁸;    -   —O—(CH₂)₂₋₃—O— wherein the oxygen atoms are bound to the phenyl        moiety in ortho-position to each other;    -   phenyloxy or benzyloxy wherein the phenyl moieties optionally        contain one further substituent selected from the group        consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, F, Cl, Br, and NO₂;    -   phenyl, optionally substituted with CN; and    -   benzoxazolyl;    -   (ii) napthyl, optionally having 1 to 3 further substituents        selected from the group consisting of        -   F, Cl, Br;        -   C₁₋₆-alkyl;        -   C₁₋₆-alkoxy;        -   CF₃; and        -   NR⁶R⁷ (wherein R⁶ and R⁷ are as defined above); or    -   (iii) phenanthrenyl;-   R⁶ and R⁷ independently from each other denote hydrogen, C₁₋₆-alkyl    or, together with the nitrogen atom to which they are attached, form    a 5- to 7-membered saturated heterocyclyl which can contain up to 3    further hetero atoms selected from the group consisting of N, O, and    S, and which saturated heterocyclyl can contain 1 to 3 substituents    selected from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy,    C₆₋₁₀-aryl and 4- to 9-membered aromatic heterocyclyl containing 1    to 4 hetero atoms selected from the group consisting of N, O, and S;    and-   R⁸ denotes hydrogen, C₁₋₆-alkyl or C₆₋₁₀-aryl-C₁₋₆-alkyl-   with the proviso that    8,9-dimethoxy-3-methyl-2-phenyl-5,6-dihydro-pyrrolo-[2.1-a]-isoquinoline-1-carboxylic    acid ethyl ester is excluded,-   and an isomer, a (pharmaceutically acceptable) salt, a hydrate or a    hydrate of a (pharmaceutically acceptable) salt thereof.

A further alternative embodiment of the present invention relates tocompounds of formula (I), wherein

-   x and y independently from each other denote zero or 1 with the    proviso that x+y=1 or 2;-   R¹ and R² independently from each other denote hydrogen, C₁₋₄-alkyl    or CF₃ or-   R¹ and R² together form a methylene bridge;-   R³ and R⁴ independently from each other denote C₁₋₄-alkyl;-   R⁵ denotes    -   (i) phenyl, optionally having 1 to 3 further substituents        selected from the group consisting of        -   F, Cl, Br;        -   CH₃, C₂H₅, i-C₃H₇;        -   OCH₃, OC₂H₅, i-OC₃H₇;        -   phenyloxy-C₁₋₄-alkoxy;        -   OH;        -   NO₂;        -   CN;        -   CF₃;        -   OCF₃;        -   NR⁶R⁷;        -   SR⁸;        -   —O—(CH₂)₂₋₃—O— wherein the oxygen atoms are bound to the            phenyl moiety in ortho-position to each other;        -   phenyloxy or benzyloxy wherein the phenyl moieties            optionally contain one further substituent selected from the            group consisting of C₁₋₄-alkyl, C₁₋₄-alkoxy, F, Cl, Br, and            NO₂;        -   phenyl, optionally substituted with CN; and        -   benzoxazolyl;    -   (ii) napthyl, optionally having 1 to 3 further substituents        selected from the group consisting of        -   F, Cl, Br;        -   C₁₋₄-alkoxy;        -   CF₃; and        -   NR⁶R⁷ (wherein R⁶ and R⁷ are as defined above); or    -   (iii) phenanthrenyl;-   R⁶ and R⁷ independently from each other denote hydrogen, C₁₋₆-alkyl    or, together with the nitrogen atom to which they are attached, form    a 5- to 7-membered saturated heterocyclyl; and-   R⁸ denotes hydrogen, C₁₋₄-alkyl or phenyl-C₁₋₄-alkyl-   with the proviso that    8,9-dimethoxy-3-methyl-2-phenyl-5,6-dihydro-pyrrolo-[2.1-a]isoquinoline-1-carboxylic    acid ethyl ester is excluded,-   and an isomer, a (pharmaceutically acceptable) salt, a hydrate or a    hydrate of a (pharmaceutically acceptable) salt thereof.

Compounds (I) wherein the radicals (R¹O)_(x) and (R²O)_(y) are attachedto the phenyl ring in the following positions, are particularlypreferred:

Pharmaceutically acceptable salts according to the invention arenon-toxic salts which in general are accessible by reaction of thecompounds (I) with an inorganic or organic base or acid conventionallyused for this purpose. Non-limiting examples of pharmaceuticallyacceptable salts of compounds (I) include the alkali metal salts, e.g.lithium, potassium and sodium salts, the alkaline earth metal salts suchas the magnesium and calcium salts, the quaternary ammonium salts suchas, for example, the triethyl ammonium salts, acetates, benzenesulphonates, benzoates, dicarbonates, disulphates, ditartrates, borates,bromides, carbonates, chlorides, citrates, dihydrochlorides, fumarates,gluconates, glutamates, hexyl resorcinates, hydrobromides,hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates,laurates, malates, maleates, mandelates, mesylates, methylbromides,methylnitrates, methylsulphates, nitrates, oleates, oxalates,palmitates, pantothenates, phosphates, diphosphates, polygalacturonates,salicylates, stearates, sulphates, succinates, tartrates, tosylates,valerates, and other salts used for medicinal purposes.

The present invention includes both the individual enantiomers ordiastereomers and the corresponding racemates, diastereomer mixtures andsalts of the compounds according to the invention. In addition, allpossible tautomeric forms of the compounds described above are includedaccording to the present invention. The diastereomer mixtures can beseparated into the individual isomers by chromatographic processes. Theracemates can be resolved into the respective enantiomers either bychromatographic processes on chiral phases or by resolution.

In the context of the present invention, the substituents, if not statedotherwise, in general have the following meaning:

Alkyl per se as well as the prefixes “alkyl” and “alk” in the terms“alkylcarbonyl”, “alkylsulphonyl”, “alkylaminocarbonylamino”, “alkoxy”and “alkoxycarbonyl” represent a linear or branched alkyl radicalpreferably having 1 to 12, more preferably 1 to 6 carbon atoms.Non-limiting examples of alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and isohexyl.

Non-limiting examples of alkylcarbonyl radicals include acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl andisobutylcarbonyl. The terms “alkylcarbonyl” and “acyl” are usedsynonymously.

Non-limiting examples of alkylsulphonyl radicals includemethylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl,butylsulphonyl and isobutylsulphonyl.

Non-limiting examples of alkylaminocarbonylamino radicals includemethylaminocarbonylamino, ethylaminocarbonylamino,propylaminocarbonylamino, isopropylaminocarbonylamino,butylaminocarbonylamino and isobutylaminocarbonylamino.

Non-limiting examples of alkoxy radicals include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy,isohexoxy. The terms “alkoxy” and “alkyloxy” are used synonymously.

Non-limiting examples of alkoxycarbonyl include methoxycarbonyl,ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,butyloxycarbonyl and isobutyloxycarbonyl.

. . . alkyl in the term “aryl-alkyl” represents a linear or branched(bivalent) alkylene radical preferably having 1 to 4 carbon atoms.Non-limiting examples include methylene, 1,2-ethylene, 1,2- and1,3-propylene, and 1,2-, 1,3-, 1,4- and 2,3-butylene; methylene ispreferred.

Alkylene represents a linear or branched (bivalent) alkylene radicalpreferably having 1 to 4 carbon atoms. Non-limiting examples of alkyleneradicals include methylene, ethylene, propylene, α-methylethylene,β-methylethylene, α-ethylethylene, β-ethylethylene, butylene,α-methylpropylene, β-methylpropylene, and γ-methylpropylene.

Cycloalkyl represents a saturated cycloalkyl radical preferably having 3to 8 carbon atoms. Non-limiting examples of cycloalkyl radicals includecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;cyclopropyl, cyclopentyl and cyclohexyl are preferred.

Aryl per se and in the terms “aryloxy”, “aryl-alkyl” and“arylaminocarbonylamino” represents an aromatic radical preferablyhaving 6 to 14, more preferably 6 to 10 carbon atoms. Non-limitingexamples of aryl radicals include phenyl, naphthyl and phenanthrenyl;non-limiting examples of aryloxy radicals include phenyloxy;non-limiting examples of aryl-alkyl radicals include benzyl;non-limiting examples of arylaminocarbonylamino radicals includephenylaminocarbonylamino, benzylaminocarbonylamino,naphthylaminocarbonylamino, and phenanthrenylaminocarbonylamino.

Heterocyclyl in the context of the invention represents a saturated,partially unsaturated or aromatic preferably 4- to 9-membered, forexample 5- to 6-membered ring which can contain 1 to 4 hetero atoms fromthe group consisting of S, N and O which ring can be bound via a carbonatom or a nitrogen atom, if such an atom is present. Non-limitingheterocyclyl examples include oxadiazolyl, thiadiazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, chinolinyl, isochinolinyl,indolyl, thienyl, furyl, pyrrolyl, N-methylpyrrolyl, indazolyl,benzimidazolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl,tetrahydrofuranyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, imidazolyl,morpholinyl, thiomorpholinyl or piperidyl. Preferred examples includethiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl,pyridazinyl and tetrahydropyranyl. The terms “heteroaryl” and “hetaryl”denote an aromatic heterocyclic radical.

Halogen in the context of the invention represents fluorine, chlorine,bromine and iodine.

The present invention also relates to a process for manufacturing thecompounds according to the invention comprisingthe reaction of a compound of the formula

wherein

-   x, y, R¹, R² and R⁴ are as defined above,-   [A] with compounds of the formulae    wherein-   R³ and R⁵ are as defined above, or-   [B] with a compound of the formula    wherein-   R³ and R⁵ are as defined above,-   and optionally-   [C] the conversion of compound (I) obtained through either process    [A] or [B] into an isomer, a (pharmaceutically acceptable) salt, a    hydrate or a hydrate of a (pharmaceutically acceptable) salt    thereof.

The compounds (II) are commercially available or can be synthesizedaccording to methods commonly known to those skilled in the art (I. T.Harrison and S. Harrison, Compendium of Organic Synthetic Methods,Wiley-Interscience, pp. 132-176; T. D. Harris and G. P. Roth, J. Org.Chem. 44, 146 (1979); E. Müller (Ed.), “Methoden der Organischen Chemie”(Houben-Weyl), Vol. VII/1 Sauerstoff-Verbindungen II, Georg ThiemeVerlag, Stuttgart 1954).

The compounds (III) are commercially available.

The compounds (IV) can be synthesized by reacting compounds of theformula

wherein

-   x, y, R¹ and R² are as defined above,-   with compounds of the formula    wherein-   R⁴ is as defined above and-   L is a leaving group, for example a halogen radical such as Cl, or a    radical of the formula    to give compounds of the formula    wherein-   x, y, R¹, R² and R⁴ are as defined above,-   and reacting compound (VIII) with a dehydrating agent.

The compounds (VI) are commercially available or can be synthesizedaccording to methods commonly known to those skilled in the art (Mayeret al., Heterocycles 31, 1035 (1990); E. Müller (Ed.), “Methoden derOrganischen Chemie” (Houben-Weyl), 4^(th) ed., Vol. 11/1Stickstoff-Verbindungen II, Georg Thieme Verlag, Stuttgart 1957; Shepardet al. in J. Org. Chem. 17, 568 (1952) and in J. Am. Chem. Soc. 72, 4364(1950)).

The compounds (VII) are commercially available or can be synthesizedaccording to methods commonly known to those skilled in the art [e.g.via acylation of acetic acid with an alkyl chloroformate or dialkylcarbonate (March, Advanced Organic Chemistry, 3^(rd) ed., p. 440-441,Wiley 1985) and converting the resulting monoester of malonic acid intoe.g. the corresponding acid chloride or anhydride by methods commonlyknown to those skilled in the art (see e.g. March, Advanced OrganicChemistry, 3^(rd) ed., p. 355, 388, Wiley 1985)].

The reaction between the compounds (VI) and (VII) is preferably carriedout in a solvent. Suitable solvents comprise the customary organicsolvents which are inert under the reaction conditions. Non-limitingexamples include ethers such as diethyl ether, dioxane, tetrahydrofuran,1,2-dimethoxy ethane; hydrocarbons such as benzene, toluene, xylene,hexane, cyclohexane, mineral oil fractions; halogenated hydrocarbonssuch as dichloromethane, trichloromethane, carbon tetrachloride,dichloroethane, trichloroethylene, chlorobenzene; ketones such asacetone; esters such as ethyl acetate; nitriles such as acetonitrile;heteroaromatics such as pyridine; polar solvents such as dimethylformamide or hexamethyl phosphoric acid tris-amide; and mixturesthereof. Dichloromethane is preferred.

Compound (VII) is generally employed in an amount of from 1 to 4 mol permol of compound (VI); an equimolar amount or slight excess of compound(VII) is preferred.

The reaction between the compounds (VI) and (VII) is preferably carriedout in the presence of a base. Non-limiting examples embrace alkalimetal hydrides and alkali metal alkoxides such as, for example, sodiumhydride and potassium tert.-butoxide; C₁₋₄-alkyl amines such as, forexample, triethyl amine; cyclic amines such as, for example, piperidine,pyridine, dimethylamino pyridine;and—preferably—1,8-diazabicyclo[4.3.0]undec-7-ene (DBU). The base isgenerally employed in an amount of from 1 to 4 mol per mol of compound(VI); an equimolar amount or slight excess of the base is preferred.

The reaction of the compounds (VI) and (VII) can generally be carriedout within a relatively wide temperature range. In general, the reactionis carried out within a range of from −20 to 200° C., preferably from 0to 70° C., and more preferably at room temperature.

For the cyclization of the compounds (VIII) to yield compounds (IV),dehydrating agents such as, for example, P₂O₅ or POCl₃ are generallyemployed in an amount of from 1 to 10 mol, preferably from 3 to 8 mol,per mol of compound (VIII).

The cyclization reaction of the compounds (VIII) to yield the compounds(IV) is also preferably carried out in a solvent. Non-limiting examplescomprise the customary organic solvents which are inert under thereaction conditions. They preferably include ethers such as diethylether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane; hydrocarbons suchas benzene, toluene, xylene, hexane, cyclohexane, mineral oil fractions;halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethane, trichloroethylene, chlorobenzene;esters such as ethyl acetate; ketones such as acetone; nitriles such asacetonitrile; heteroaromatics such as pyridine; polar solvents such asdimethyl formamide and hexamethyl phosphoric acid tris-amide; andmixtures thereof. Toluene is preferred, if the reaction is carried outwith P₂O₅, and acetonitrile is preferred, if the reaction is carried outwith POCl₃ (Benovsky, Stille, Tetrahedron Lett. 38, 8475-8478 (1997)).

The temperature for the cyclization reaction of compounds (VIII) ispreferably within a range of from 60 to 200° C. and more preferablywithin a range of from 80 to 120° C.

The above process steps are generally carried out under atmosphericpressure. However, it is also possible to carry them out undersuperatmospheric pressure or under reduced pressure (for example, in arange of from 0.5 to 5 bar). The reaction time can generally be variedwithin a relatively wide range. In general, the reaction is finishedafter a period of from 2 to 24 hours, preferably from 6 to 12 hours.

The reaction of the compounds (IV) with either compounds (II) and (III)or with compound (V) can be carried out as a one-pot synthesis,preferably in a solvent. Suitable solvents comprise the customaryorganic solvents which are inert under the reaction conditions.Non-limiting examples include ethers such as diethyl ether, dioxane,tetrahydrofuran, 1,2-dimethoxy ethane; hydrocarbons such as benzene,toluene, xylene, hexane, cyclohexane, mineral oil fractions; halogenatedhydrocarbons such as dichloromethane, trichloromethane, carbontetrachloride, dichloroethane, trichloroethylene, chlorobenzene;alcohols such as methanol, ethanol, n-propanol, isopropanol; esters suchas ethyl acetate; ketones such as acetone; nitrites such asacetonitrile; heteroaromatics such as pyridine; polar solvents such asdimethyl formamide and hexamethyl phosphoric acid tris-amide; andmixtures thereof. Ethanol/isopropanol (approximately 1:1 vol/vol)mixtures are preferred.

The compounds (III) are generally employed in an amount of from 1 to 3mol per mol of compound (II); an equimolar amount or slight excess ofcompound (III) is particularly preferred. The compounds (IV) aregenerally employed in an amount of from 0.1 to 1 mol, preferably from0.3 to 1 mol, per mol of compounds (II).

The reactions of the compounds (IV) with either compounds (II) and (III)or with compound (V) are preferably carried out in the presence of abase. Non-limiting examples include alkali metal hydrides and alkalimetal alkoxides such as, for example, sodium hydride and potassiumtert.-butoxide; C₁₋₄-alkyl amines such as, for example, triethyl amine;cyclic amines such as, for example, pyridine, dimethylamino pyridine,1,8-diazabicyclo[4.3.0]undec-7-ene (DBU) and—preferably—piperidine. Thebase is generally employed in an amount of from 0.1 to 1 mol, preferablyfrom 0.3 to 1 mol, per mol of compound (II) or compound (V),respectively.

The reactions of the compounds (IV) with either compounds (II) and (III)or with compound (V) are generally carried out within a relatively widetemperature range. In general, they are carried out in a range of from−20 to 200° C., preferably from 0 to 100° C., and more preferably from50 to 90° C. The steps of this reaction are generally carried out underatmospheric pressure. However, it is also possible to carry them outunder superatmospheric pressure or under reduced pressure (for example,in a range of from 0.5 to 5 bar). The reaction time can generally bevaried within a relatively wide range. In general, the reaction isfinished after a period of from 2 to 24 hours, preferably from 6 to 12hours.

The compounds (V) are commercially available or can be synthesized inanalogy to the reaction of compounds (II) and (III) described above (inthe absence of compound (IV).

The process according to the present invention can be illustrated by thefollowing scheme:

wherein

-   x, y, R¹ to R⁵, and L are as defined above.

The compounds of the present invention are inhibitors ofphosphodiesterase 10a (PDE 10a). As outlined above, the inhibition ofPDE 10a is a promising approach for the treatment of cancer. Thebiological tests described below show that the compounds according tothe invention exhibit a pronounced anti-proliferation activity againsttumor cells; they are therefore useful for the treatment of cancer.Furthermore, our investigations showed that they are also useful fortreatment of conditions of pain and/or for the lowering of thetemperature of the body in fever conditions.

The compounds according to the invention can be used as activeingredients for the production of medicaments against carcinomatousdisorders. For this, they can be converted into the customaryformulations such as tablets, coated tablets, aerosols, pills, granules,syrups, emulsions, suspensions and solutions using inert, non-toxic,pharmaceutically suitable excipients or solvents. Preferably, thecompounds according to the invention are used in an amount such thattheir concentration is approximately 0.5 to approximately 90% by weight,based on the ready-to-use formulations, the concentration beingdependent, inter alia, on the indication of the medicament.

The formulations can be produced, for example, by extending the activecompounds with solvents and/or excipients having the above properties,where, if appropriate, additionally emulsifiers or dispersants and, inthe case of water as the solvent, an organic solvent can additionally beadded.

Administration can be carried out in a customary manner, preferablyorally, transdermally or parenterally, for example perlingually,buccally, intravenously, nasally, rectally or inhalationally.

For human use, in the case of oral administration, it is recommended toadminister doses of from 0.001 to 50 mg/kg, preferably from 0.01 to 20mg/kg. In the case of parenteral administration such as, for example,intravenously or via mucous membranes nasally, buccally orinhalationally, it is recommended to use doses of 0.001 to 0.5 mg/kg.

If appropriate, it may be necessary to depart from the amounts mentionedabove, namely depending on the body weight or the type of administrationroute, on the individual response towards the medicament, the manner ofits formulation and the time or interval at which administration takesplace. Thus, in some cases it may be sufficient to manage with less thanthe above mentioned minimum amount, while in other cases the upper limitmentioned must be exceeded. In the case of the administration ofrelatively large amounts, it may be recommended to divide these intoseveral individual doses over the course of the day.

The compounds according to the invention are also suitable for use inveterinary medicine. For use in veterinary medicine, the compounds ortheir non-toxic salts can be administered in a suitable formulation inaccordance with general veterinary practice. Depending on the kind ofanimal to be treated, the veterinary surgeon can determine the nature ofuse and the dosage.

The present invention provides compounds for the use in a medicalapplication, in particular for combating cancer.

The invention further provides a method of manufacturing apharmaceutical composition by combining at least one of the compounds ofthe invention with at least one pharmacologically acceptable formulatingagent.

The invention further provides a pharmaceutical composition comprisingas an active ingredient an effective amount of at least one of thecompounds of the invention and at least one pharmacologically acceptableformulating agent.

The invention further provides a pharmaceutical composition comprisingas an active ingredient an effective amount of at least one of thecompounds of the invention and at least one pharmaceutical activeingredient which is different from the compounds of the invention.

The invention further provides a medicament in dosage unit formcomprising an effective amount of a compound according to the inventiontogether with an inert pharmaceutical carrier.

The invention further provides a method of combating cancer in mammalscomprising the administration of an effective amount of at least onecompound according to the invention either alone or in admixture with adiluent or in the form of a medicament.

The percentages in the following tests and in the Examples are—if notstated otherwise—percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentrations in solutions ofliquids in liquids are ratios by volume.

Biological Tests

In vitro Enzyme Inhibition Assay:

Full-length recombinant PDE 10a was expressed in Sf9 insect cells(Invitrogen, Carlsbad, Calif., U.S.A.) using the Bac-to-Bac™ BaculovirusExpression System (Life Technologies, Gaithersburg, Md., U.S.A.). 48hours post infection, cells were harvested and resuspended in 20 mL (per1 L culture) Lysis Buffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 mMMgCl₂, 1.5 mM EDTA, 10% glycerol plus 20 μL Protease Inhibitor CocktailSet III [CalBiochem, La Jolla, Calif., U.S.A.]). Cells were sonicated at4° C. for 1 minute and centrifuged at 10,000 RPM for 30 minutes at 4° C.Supernatant was removed and stored at −20° C. for activity assays.

The test compounds were serially diluted in DMSO using two-folddilutions to stock concentrations ranging typically from 200 μM to 1.6μM (final concentrations in the assay range from 4 μM to 0.032 μM).96-well assay isoplates (Wallac Inc., Atlanta, Ga., U.S.A.) were loadedwith 50 μL dilution buffer per well (dilution buffer: 50 mM Tris/HCl pH7.5, 8.3 mM MgCl₂, 1.7 mM EDTA, 0.2% BSA). 2 μL of the serially dilutedindividual test compounds were added to individual wells,m followed by25 μL of a 1:25,000 dilution of crude recombinant PDE 10a-containing Sf9cell lysate (diluted in dilution buffer described above). The enzymaticassay was initiated by addition of 25 μL (0.025 μCi) ³H cyclic AMPtracer [5′,8-³H] adenosine 3′,5′-cyclic phosphate (Amersham PharmaciaBiotech., Piscataway, N.J., U.S.A.) that was diluted 1:1000 in assaybuffer (assay buffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl₂, 1.7 mM EDTA).Reactions were incubated at room temperature for 60 minutes andterminated by addition of 25 μL of 18 mg/mL Yttrium ScintillationProximity Beads (Amersham Pharmacia Biotech., Piscataway, N.J., U.S.A.).Plates were sealed and incubated at room temperature for 60 minutes.Plates were read for 30 seconds/well using a Microbeta counter (WallacInc., Atlanta, Ga., U.S.A.). The IC₅₀ values were determined by plottingcompound concentration versus percent inhibition. Representative resultsare shown in Tables 1a and 1b:

TABLE 1a Example (part a) No. IC₅₀ (nM) 1 30 6 56 7 81 8 46 9 490 10 4215 62 25 96 28 110

TABLE 1b Example (part b) No. IC₅₀ (nM) 1 110 19 34 20 32 49 270In vitro Proliferation Inhibition Assay:

MDA-MB-231 human breast carcinoma cells (ATCC # HTB26) were cultured instandard growth medium (DMEM), supplemented with 10% heat-inactivatedFBS, 10 mM HEPES, 2 mM glutamine, 100 U/mL penicillin, and 100 μg/mLstreptomycin) at 37° C. in 5% CO₂ (vol/vol) in a humidified incubator.Cells were plated at a density of 3000 cells per well in 100 μL growthmedium in a 96 well culture dish. 24 hours after plating, LDH activitywas determined using the Cytotox 96 Non-radioactive Cytotoxicity Kit(Promega, Madison, Wis., U.S.A.) to yield T_(0h) LDH values. Briefly,cells were lysed with the addition of 200 μL of Lysis Buffer (includedin the Promega Kit) and lysates were further diluted 1:50 in LysisBuffer. 50 μL of diluted cell lysate were transferred to a fresh 96 wellculture plate. The assay was initiated with the addition of 50 μL ofsubstrate per well. Color development was allowed to proceed for 10-15minutes. The assay was terminated with the addition of 50 μL of StopSolution (included in Promega kit). Optical densities were determinedspectrophotometrically at 490 nm in a 96 well plate reader (SpectraMax250, Molecular Devices, Sunnyvale, Calif., U.S.A.).

Test compounds were dissolved in 100% DMSO to prepare 10 mM stocks.Stocks were further diluted 1:250 in growth medium to yield workingstocks of 40 μM test compound in 0.4% DMSO. Test compounds were seriallydiluted in growth medium containing 0.4% DMSO to maintain constant DMSOconcentrations for all wells. 50 μL of fresh growth medium and 50 μL ofdiluted test compound were added to each culture well to give a finalvolume of 200 μL. The cells with and without individual test compoundswere incubated for 72 hours at which time LDH activity was measured toyield T_(72h) values. Optionally, the IC₅₀ values can be determined witha least squares analysis program using compound concentration versuspercent inhibition.% Inhibition=[1−(T _(72h test) −T _(0h))/(T _(72h ctrl) −T _(0h))]×100wherein

-   T_(72h test)=LDH activity at 72 hours in the presence of test    compound,-   T_(72h ctrl)=LDH activity at 72 hours in the absence of test    compound and-   T_(0h)=LDH activity at Time Zero

Representative results are shown in Tables 2a and 2b below:

TABLE 2a % inhibition at a concentration Example (part a) No. of 10 μM 193 6 97 7 96 8 96 9 94 10 93 15 92 25 88 28 93

TABLE 2b Example (part b) % inhibition at a concentration No. of 10 μM 189 19 87 20 86 49 58In vivo Tumor Growth Inhibition Assay:

Inhibition of tumor growth in vivo is readily determined via thefollowing assay:

MDA-MB-231 cells are cultured as described above. The cells wereharvested by trypsinization, washed, counted, adjusted to 2.5×10⁷cells/mL with ice-cold PBS, and subsequently stored on ice untiltransplantation. Xenograft experiments are conducted using eight-to-tenweek-old female athymic mice with an average body mass of 20-25 g.Approximately 5×10⁶ cells in a total volume of 0.2 mL PBS were injectedsubcutaneously in the flank region. Thereafter the mice were randomizedand divided into several groups that reflect different dosages orschedules, respectively (n=10 mice/group). The test compounds wereadministered starting at day 1 at different dosages (e.g. 10, 20 and 40mg/kg) and different schedules (e.g. Q1D×15, Q2D×7, Q3D×5). Testcompounds were formulated for oral administration in a vehicle for oraladministration composed of polyethylene glycol-400, ™Cremophor, ethanoland 0.9% saline (40:5:5:50). Tumor measurements were performed twice perweek. Tumor weights are calculated using the formula (a×w²)/2. Animalswere sacrificed on day 15 after transplantation and plasma was harvestedfor pharmacokinetic analyses.

Abbreviations used in this Specification

BSA bovine serum albumin ™ Cremophor non-ionic emulsifyer from BASF DBU1,8-diazabicyclo[5.4.0]undec-7-ene DMEM Dulbecco's Modified EagleMedium, Life Technologies, Gaithersburg, MD, U.S.A. DMF N,N-dimethylformamide DMSO dimethyl sulphoxide EDTA ethylene diamine tetraacetateFBS fetal bovine serum HEPES N-(2-hydroxyethyl)-piperazine-N′-(2- ethanesulphonic acid) HPLC high pressure liquid chromatography LC-MS liquidchromatography - coupled mass spectroscopy LDH lactate dehydrogenase NMRnuclear resonance spectroscopy PBS phosphate-buffered saline tlc thinlayer chromatography Tris/HCl tris(hydroxymethyl)-aminomethanehydrochloride ™ Triton X-100 tert.-octylphenoxypolyethoxyethanol

The yield percentages of the following Examples refer to the startingcomponent which was used in the lowest molar amount.

EXAMPLES A. LC-MS/HPLC Methods

Method A: MS equipment: Micromass Quattro LCZ ionisation mode: ESIpositive/negative HPLC equipment: HP 1100 UV detection: 208-400 nmtemperature: 40° C. Column: ™ Symmetry C 18 50 mm × 2.1 mm 3.5 μmSupplier: Waters Time Flow Gradient: [min.] A: % B: % [mL/min.] 0.0010.0 90.0 0.50 4.00 90.0 10.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.01.00 7.50 10.0 90.0 0.50 A: 0.1% strength solution of formic acid inacetonitrile B: 0.1% strength aqueous formic acid

Method B: Column: ™ Kromasil C 18 60 mm × 2.0 mm Time Flow Gradient:[min.] A: % B: % [mL/min.] 0.00 90.0 10.0 0.75 0.50 90.0 10.0 0.75 4.5010.0 90.0 0.75 6.50 10.0 90.0 0.75 7.50 90.0 10.0 0.75 A: 0.001%strength aqueous H₃PO₄ B: acetonitrile

Method C: MS equipment: Micromass TOF-MUX- Interface 4-fold parallelinjection ionisation mode: ESI positive HPLC equipment: Waters 600 UVdetection: 210 nm temperature: 40° C. Column: Symmetry C 18 50 mm × 2.1mm 3.5 μm Supplier: Waters Time Flow Gradient: [min.] A: % B: %[mL/min.] 0.00 10.0 90.0 0.75 0.50 10.0 90.0 0.75 4.00 90.0 10.0 0.755.50 90.0 10.0 0.75 5.60 10.0 90.0 1.25 6.50 10.0 90.0 0.75 A: 0.1%strength solution of formic acid in acetonitrile B: 0.1% strengthaqueous formic acid

Method D: MS equipment: Micromass Platform LCZ ionisation mode: ESIpositive/negative HPLC equipment: HP 1100 UV detection: 208-400 nmtemperature: 40° C. Column: Symmetry C 18 50 mm × 2.1 mm 3.5 μmSupplier: Waters Time Flow Gradient: [min.] A: % B: % [mL/min.] 0.0010.0 90.0 0.50 4.00 90.0 10.0 0.50 6.00 90.0 10.0 0.50 6.10 10.0 90.01.00 7.50 10.0 90.0 0.50 A: 0.1% strength solution of formic acid inacetonitrile B: 0.1% strength aqueous formic acid

Method E: Column: Kromasil C 18 60 mm × 2.0 mm Time Flow Gradient:[min.] A: % B: % [mL/min.] 0.00 98.0 2.0 0.75 4.50 10.0 90.0 0.75 6.5010.0 90.0 0.75 6.70 98.0 2.0 0.75 7.50 98.0 2.0 0.75 A: 0.5% strengthaqueous HClO₄ B: acetonitrile

B. Starting Materials

I. Phenethyl Amines

The substituted 2-phenethyl amines are commercially available or can beprepared in analogy to anyone of the following procedures, e.g. startingfrom the corresponding benzaldehydes (see also Shepard et al. in J. Org.Chem. 17, 568 (1952) and in J. Am. Chem. Soc. 72, 4364 (1950)).

I.1. 2-[3-(Trifluoromethoxy)-phenyl]-ethyl amine

2-[3-(Trifluoromethoxy)-phenyl]-ethyl amine was obtained byhydrogenation of 3-[3-(trifluoromethoxy)-phenyl]-acetonitrile in analogyto the method described by Shepard et al. in J. Org. Chem. 17, 568(1952) and in J. Am. Chem. Soc. 72, 4364 (1950).

I.2 2-(3-Methoxy-4-propoxyphenyl)-ethyl amine

2-(3-Methoxy-4-propoxyphenyl)-ethyl amine was obtained starting from3-methoxy-4-hydroxy-benzaldeyde, alkylation with n-propyl bromide(Dickinson et al, J. Chem. Soc. 1927, 1894) and then following thesequence described by Shepard et al. in J. Org. Chem. 17, 568 (1952) andin J. Am. Chem. Soc. 72, 4364 (1950).

II. Amides

II.1. Ethyl 3-{[2-(3,4-dimethoxyphenyl)-ethyl]-amino}-3-oxopropanoate

A solution of 12.4 g (82.7 mmol) of ethyl 3-chloro-3-oxopropanoate in150 mL of dichloromethane was added at room temperature to a solution of15.0 g (82.7 mmol) of 2-(3,4-dimethoxyphenyl)-ethyl amine and 12.6 g(82.7 mmol) of DBU in 300 ml of dichloromethane. The mixture was stirredat room temperature overnight, then water was added, and the organiclayer was washed three times with water. The organic phase was driedover Na₂SO₄, and the solvent was evaporated under reduced pressure togive the title compound.

Yield: 91.3%.

¹H NMR (400 MHz, CDCl₃):

δ=1.26 (t, J=7.1 Hz, 3H), 2.78 (t, J=7.0 Hz, 2H), 3.27 (s, 2H), 3.53 (q,J=6.0 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.16 (q, J=7.1 Hz, 2H),6.70-6.76 (m, 2H), 6.81 (d, J=8.7 Hz, 1H), 7.12 (s, 1H).

The following amides were obtained according to an analogous procedure:

II.2. Methyl 3-{[2-(3,4-dimethoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.3. Ethyl3-{[2-(3-methoxy-4-ethoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.4. Ethyl3-{[2-(3-methoxy-4-propoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.5. Methyl3-{[2-(2-methoxy-3-methoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.6. Ethyl 3-{[2-(5-methoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.7. Ethyl3-{[2-(3-ethoxy-4-methoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.8. Ethyl 3-{[2-(3-methoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.9. Ethyl 3-{[2-(3,5-dimethoxyphenyl)-ethyl]-amino}-3-oxopropanoate

II.10. Ethyl 3-[(2-phenylethyl)-amino]-3-oxopropanoate

II.11. Ethyl 3-{[2-(1,3-benzodioxol-5-yl)-ethyl]-amino}-3-oxopropanoate

II.12. Ethyl3-oxo-3-({2-[3-(trifluoromethoxy)-phenyl]-ethyl}-amino)-propanoate

III. (3,4-Dihydro-1(2H)-isoquinolinylidene)-ethanoates

III.1. Ethyl(6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate

A solution of 22.0 g (74.5 mmol) of ethyl3-{[2-(3,4-dimethoxyphenyl)-ethyl]-amino}-3-oxopropanoate Example II.1)in 400 mL of toluene was heated under reflux, and 63.4 g (446.95 mmol)of phosphorus pentoxide were added to the boiling solution in 6 portionsat 15-20 min. intervals (following the course of the reaction by tlcusing a cyclohexane/ethyl acetate 1:1 mixture as eluant). After coolingto room temperature, the bulk of toluene was decanted and residualtoluene was removed by evaporation under reduced pressure. Solid ice wasadded to the residue, and the mixture was stirred at room temperature.The resulting solution was filtered and extracted several times withethyl acetate. The combined organic phases were dried over Na₂SO₄,filtered through a pad of silica gel, and finally the solvent wasevaporated under reduced pressure to give the title compound.

Yield: 87.1%.

¹H NMR (200 MHz, CDCl₃):

δ=1.30 (t, J=7.2 Hz, 3H), 2.83 (t, J=6.4 Hz, 2H), 3.32-3.52 (m, 2H),3.89 (s, 3H), 3.91 (s, 3H), 4.17 (q, J=7.1 Hz, 2H), 5.05 (s, 1H), 6.66(s, 1H), 7.12 (s, 1H), 9.04 (s, 1H).

The following (3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoates wereobtained according to an analogous procedure:

-   III.2 Methyl    (2E,Z)-(6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)ethanoate-   III.3 Ethyl    (2E,Z)-(7-ethoxy-6-methoxy-3,4-dihydro-1(2H)-isoquinolinylidene)ethanoate-   III.4 Ethyl    (2E,Z)-(6-ethoxy-7-methoxy-3,4-dihydro-1(2H)-isoquinolinylidene)ethanoate-   III.5 Ethyl    (2E,Z)-(7-butoxy-6-methoxy-3,4-dihydro-1(2H)-isoquinolinylidene)ethanoate-   III.6 Methyl    (2E,Z)-(5,6-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)ethanoate-   III.7 Methyl    (2E,Z)-[6-(trifluoromethoxy)-3,4-dihydro-1(2H)-isoquinolinylidene]ethanoate-   III.8 Ethyl    (2E,Z)-(6,8-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate-   III.9 Ethyl (2E,Z)-(3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate-   III.10 Ethyl    (2E,Z)-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-ylideneethanoate-   III.11 Ethyl    (2E,Z)-(6-methoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (A)    and ethyl    (2E,Z)-(8-methoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate    (B):

A solution of 44.10 g (170 mmol) of ethyl3-{[2-(3-methoxyphenyl)-ethyl]-amino}3-oxopropanoate (prepared asdescribed in II.8 from 3-methoxy-phenylethyl amine and ethyl3-chloro-3-oxoproanoate with 95.8% yield) in 432 mL of toluene washeated under reflux, and 179.31 g (1260 mmol) of phosphorus pentoxidewere added to the boiling solution in 6 portions at 15-20 min. intervals(following the course of the reaction by tlc using a cyclohexane/ethylacetate 1:1 mixture as eluant). After cooling to room temperature, 1 Lof water was added slowly with ice cooling, then the resulting mixturewas made alcaline by adding potassium carbonate. The mixture wasextracted 4 times with ether, the combined organic phases were driedover Na₂SO₄, filtered, and the solvent was evaporated. Compounds A and Bwere separated by silica gel chromatography: 20.5 g (48.89%) of compoundA and 620 mg (1.51%) of compound B were obtained.

C. Preparation Examples

Part a

Example 1 Ethyl2-(4-hydroxy-3,5-dimethylphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylate

A mixture of 500 mg (1.8 mmol) of ethyl(6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (ExampleIII.1), 558 mg (3.61 mmol) of 3,5-dimethyl-4-hydroxybenzaldehyde, 281 mg(3.61 mmol) of nitroethane and 61.4 mg (0.72 mmol) of piperidine in 10mL of an ethanol/isopropanol 1:1 mixture was stirred at 80° C.overnight. 40 mL of isopropanol were added, the mixture was cooled to 0°C., and the resulting precipitate was filtered off. The solid was washedwith ethanol and dried in vacuo to give the title compound as a whitesolid which was readily recrystallized from ethyl acetate to furnishwhite needles.

Yield: 673 mg.

¹H NMR (200 MHz, CDCl₃):

δ=0.96 (t, J=7.2 Hz, 3H), 2.17 (s, 3H), 2.21 (s, 6H), 2.98 (t, J=6.4 Hz,2H), 3.77-3.98 (m, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 4.06 (q, J=7.2 Hz,2H), 4.56 (s, 1H), 6.71 (s, 1H), 6.88 (s, 2H), 7.88 (s, 1H).

The following Preparation Examples (Nos. 2-25) were prepared in analogyto Example 1:

Ex. No. Structure Analytical data 2

Melting point [° C.]: 127-129 3

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.97(t, J=7.2 Hz, 3H), 2.12(s, 3H),2.94(t, J= 6.4 Hz, 2H), 3.72(s, 3H), 3.79(s, 3H), 3.92(t, J=6.6 Hz, 2H),4.02(q, J=7.2 Hz, 2H), 5.39(s, 2H), 6.93(s, 1H), 7.02(s, 2H), 7.66(s,1H) MS: 475[M + H]⁺ HPLC retention time [min.]: 4.78(method A) 4

MS: 458[M + H]⁺ HPLC retention time [min.]: 4.42(method A) 5

MS: 472[M + H]⁺ HPLC retention time [min.]: 4.57(method A) 6

Melting point [° C.]: 202-204 7

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.93(t, J=7.2 Hz, 3H), 2.11(s, 3H),2.94(t, J=6.4 Hz, 2H), 3.72(s, 3H), 3.79(s, 3H), 3.92(t, J= 6.6 Hz, 2H),3.99(q, J=7.2 Hz, 2H), 6.89-7.99(m, 3H), 7.09(s, 1H), 7.66(s, 1H),9.95(s, 1H) MS: 442[M + H]⁺ HPLC retention time [min.]: 4.25(method A) 8

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.92(t, J=7.2 Hz, 3H), 2.11(s,3H), 2.12(s,3H), 2.94(t, J=6.4 Hz, 2H), 3.71(s, 3H), 3.78(s, 3H), 3.91(t, J=6.6 Hz,2H), 3.97(q, J=7.2 Hz, 2H), 6.70-6.95(m, 4H), 7.60(s, 1H), 9.08(s, 1H)MS: 422[M + H]⁺ HPLC retention time [min.]: 4.49(method B) 9

MS: 428[M + H]⁺ HPLC retention time [min.]: 4.88(method A) 10

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.90(t, J=7.0 Hz, 3H), 2.16(s, 3H),2.88(s, 6H), 2.95(t, J=6.4 Hz, 2H), 3.72(s, 3H), 3.79(s, 3H),3.89-4.03(m, 4H), 6.44-6.53(m, 2H), 6.60-6.67(m, 1H), 6.94(s, 1H),7.15(t, J=8.1 Hz, 1H), 7.60(s, 1H) MS: 435[M + H]⁺ HPLC retention time[min.]: 4.07(method C) 11

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.88(t, J=7.0 Hz, 3H), 2.14(s, 3H),2.96(t, J=6.4 Hz, 2H), 3.73(s, 3H), 3.79(s, 3H), 3.88-4.03(m, 4H),6.91-7.14(m, 4H), 7.33-7.44(m, 1H), 7.72(s, 1H) MS: 410[M + H]⁺ HPLCretention time [min.]: 5.15(method C) 12

Melting point [° C.]: 192-193 13

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.91(t, J=7.2 Hz, 3H), 1.36(s, 9H),2.14(s, 3H), 2.19(s, 3H), 2.94(t, J=6.4 Hz, 2H), 3.71(s, 3H), 3.78(s,3H), 3.87-4.01(m, 4H), 6.78(d, J=1.7 Hz, 1H), 6.81(d, J=1.9 Hz, 1H),6.93(s, 1H), 7.57(s, 1H), 7.92(s, 1H) MS: 478[M + H]⁺ HPLC retentiontime [min.]: 5.28(method C 14

Melting point [° C.]: 152-153 15

Melting point [° C.]: 225-226 16

¹H-NMR(400 MHz, CDCl₃): δ = 0.97(t, J=7.1 Hz, 3H), 2.18(s, 3H),2.82-3.07(m, 8H), 3.74-3.97(m, 8H), 4.07(q, J=7.1 Hz, 2H), 6.60-6.85(m,3H), 7.16(d, J=8.1 Hz, 2H), 7.87(s, 1H) MS: 435[M + H]⁺ HPLC retentiontime [min.]: 3.68(method B) 17

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.92(t, J=7.1 Hz, 3H), 1.32(t, J=6.8 Hz,3H), 2.13(s, 3H), 2.87-3.00(m, 2H), 3.71(s, 3H), 3.78(s, 3H),3.86-4.05(m, 6H), 6.56(d, J=7.8 Hz, 1H), 6.68(s, 1H), 6.76(d, J=8.1 Hz,1H), 6.93(s, 1H), 7.59(s, 1H) MS: 452[M + H]⁺ HPLC retention time[min.]: 4.20(method A) 18

Melting point [° C.]: 96-97 19

Melting point [° C.]: 163-164 20

Melting point [° C.]: 193-194 21

Melting point [° C.]: 201-203 22

¹H-NMR(300 MHz, CDCl₃): δ = 0.95(t, J=7.2 Hz, 3H), 2.15(s, 3H), 2.98(t,J=6.6 Hz, 2H), 3.82-3.97(m, 2H), 3.90(s, 3H), 3.91(s, 3H), 4.04(q, J=7.2Hz, 2H), 4.66(s, 1H), 6.71(s, 1H), 6.83(d, J=8.7 Hz, 2H), 7.13(d, J=9.0Hz, 2H), 7.92(s, 1H) MS: 408[M + H]⁺ HPLC retention time [min.]:4.30(method B) 23

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.90(t, J=7.0 Hz, 3H), 2.14(s, 3H),2.95(t, J=6.2 Hz, 2H), 3.72(s, 3H), 3.79(s, 3H), 3.89-4.03(m, 4H),6.53-6.68(m, 3H), 6.94(s, 1H), 7.12(t, J=8.1 Hz, 1H), 7.63(s, 1H),9.21(s, 1H) MS: 408[M + H]⁺ HPLC retention time [min.]: 4.49(method C)24

HPLC retention time [min.]: 3.98(method A) 25

Melting point [° C.]: 212

Examples 26 and 27 Ethyl8-methoxy-9-hydroxy-2-(3,5-dimethyl-4-hydroxyphenyl)-3-methyl-5,6-dihydro[2,1-a]isoquinoline-1-carboxylate(Example 26) and Ethyl9-methoxy-8-hydroxy-2-(3,5-dimethyl-4-hydroxyphenyl)-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate(Example 27)

1 g (2.3 mmol) of ethyl2-(4hydroxy-3,5-dimethylphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate(Example 1) was intimately mixed with 4 g of pyridine hydrochloride andheated to fusion at 150° C. The mixture was stirred at 150° C. for 20min., then cooled to room temperature and dissolved in a mixture ofethyl acetate and dilute hydrochloric acid. The layers were separated,the aqueous layer was extracted with ethyl acetate, and the combinedorganic phases were washed with water, dried over Na₂SO₄, and thesolvent was evaporated under reduced pressure. Column chromatography onsilica gel using a dichloromethane/ethyl acetate 10:1 mixture as eluantafforded the title compounds ethyl8-methoxy-9-hydroxy-2-(3,5-dimethyl-4-hydroxyphenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylate(Example 26):

Yield: 46 mg.

Melting point [° C.]: 218-220;

and

ethyl9-methoxy-8-hydroxy-2-(3,5-dimethyl-4-hydroxyphenyl)-3-methyl-5,6-dihydro-pyrrolo[2,1-a]isoquinoline-1-carboxylate(Example 27):

Yield: 34 mg.

Melting point [° C.]: 164-165.

Example 28 Ethyl2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]-isoquinoline-1-carboxylate

4.5 g (10.31 mmol) of ethyl8,9-dimethoxy-3-methyl-2-(3-nitrophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate(Example 2) were dissolved in 500 mL of warm methanol, 2.03 g of 10%strength palladium on charcoal were added, and the compound washydrogenated at atmospheric pressure. The reaction mixture was filteredthrough a filter aid, the filtrate was evaporated under reduced pressureto a volume of approx. 150 mL, and the resulting precipitate wasfiltered off to give the title compound.

Yield: 3.36 g (80.2%).

Melting point [° C.]: 170-172.

Example 29 Ethyl8,9-dimethoxy-3-methyl-2-(3-piperidinyl-phenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylate

168.5 mg (1.11 mmol) of DBU and 84.9 mg (0.37 mmol) of1,5-dibromopentane were added to a solution of 150 mg (0.37 mmol) ofethyl2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate(Example 28) in 3 mL of DMF. The mixture was stirred at 120° C. for 20hours, then evaporated under reduced pressure, and the residue was takenup in an ethyl acetate/water mixture. The layers were separated, theaqueous layer was extracted with ethyl acetate, and the combined organicphases were washed with water, dried over Na₂SO₄, and the solvent wasevaporated under reduced pressure. Chromatography on a short silica gelcolumn using a dichloromethane/ethyl acetate 10:1 mixture as eluant,followed by crystallization from diethyl ether gave the title compound.

Yield: 65.2 mg.

Melting point [° C.]: 128-130.

Part b

Example 1 Ethyl2-(3,5-dihydroxyphenyl)-8,9-dimethoxy-3-methyl-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylate

A mixture of 500 mg (1.8 mmol) of ethyl(6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (ExampleIII.1), 499 mg (3.61 mmol) of 3,5-dihydroxybenzaldehyde, 281 mg (3.61mmol) of nitroethane and 61.4 mg (0.72 mmol) of piperidine in 10 mL ofan ethanol/isopropanol 1:1 mixture was stirred at 80° C. overnight. 40mL of isopropanol were added, the mixture was cooled to 0° C., and theresulting precipitate was filtered off. The solid was washed withethanol and dried in vacuo to give the title compound as a white solidwhich was readily recrystallized from ethyl acetate to furnish whiteneedles.

Yield: 12.9%.

¹H NMR (300 MHz, DMSO-d₆):

δ=0.96 (t, J=7.2 Hz, 3H), 2.14 (s, 3H), 2.94 (t, J=6.6 Hz, 2H), 3.71 (s,3H), 3.78 (s, 3H), 3.92 (t, J=6.6 Hz, 2H), 4.00 (q, J=7.2 Hz, 2H), 6.03(d, J=2.3 Hz, 2H), 6.09 (t, J=2.3 Hz, 1H), 6.93 (s, 1H), 7.58 (s, 1H),9.02 (s, 2H).

MS: 424.2 [M+H]⁺

HPLC retention time [min]: 4.06 (method C)

The following Preparation Examples (Nos. 2-91) were prepared in analogyto Example 1. All aldehydes are commercially available or are preparedin analogy to published procedures (I. T. Harrison and S. Harrison,Compendium of Organic Synthetic Methods, pages 132-177,Wiley-Interscience, John Wiley & Sons, Inc.). If nitropropane is usedinstead of nitroethane, ethyl3-ethyl-5,6-dihydro-pyrrolo[2,1-a]isoquinolines are obtained.

Ex. Structure Analytical data 2

¹H-NMR(300 MHz, DMSO-d₆): δ = 2.13(s, 3H), 2.94(t, 2H), 3.54(s, 3H),3.72(s, 3H), 3.77(s, 6H), 3.78(s, 3H), 3.92(t, 2H), 6.51-6.57(m, 1H),6.61(d, 1H), 6.88(d, 1H), 6.94(s, 1H), 7.44(s, 1H), 8.86(s, 1H) Meltingpoint [° C.]: 186-187 3

¹H-NMR(200 MHz, CDCl₃): δ = 0.91(t, J=7.1 Hz, 3H), 1.11(t, J=7.5 Hz,3H), 2.52(q, J=7.3 Hz, 2H), 2.99(t, J=6.3 Hz, 2H), 3.82-4.09(m, 10H),6.72(s, 1H), 6.96-7.46(m, 4H), 7.97(s, 1H) MS: 440.1[M + H]⁺ HPLCretention time [min]: 5.66(method B) 4

Melting point [° C.]: 136-137 MS: 436.1[M + H]⁺ HPLC retention time[min]: 5.2(method B) 5

¹H-NMR(300 MHz, CDCl₃): δ = 2.17(s, 3H), 3.00(t, 2H), 3.58(s, 3H),3.90-3.94(m, hidden 2H), 3.91(s, 3H), 3.92(s, 3H), 6.73(s, 1H),7.10-7.16(m, 1H), 7.18-7.33(m, 3H), 7.89(s, 1H) 6

MS: 451.3[M − H]⁺ HPLC retention time [min]: 4.02(method A) 7

MS: 468.2[M + H]⁺ HPLC retention time [min]: 4.49(method C) 8

¹H-NMR(200 MHz, CDCl₃): δ = 0.83(t, J=7.2 Hz, 3H), 1.11(t, J=7.5 Hz,3H), 2.52(q, J=7.6 Hz, 2H), 3.00(t, J=6.6 Hz, 2H), 3.86-4.07(m, 4H),3.91(s, 3H), 3.92(s, 3H), 6.73(s, 1H), 7.35-7.61(m, 4H), 8.00(s, 1H) MS:474.2[M + H]⁺ HPLC retention time [min]: 5.7(method B) 9

¹H-NMR(200 MHz, CDCl₃): δ = 0.85(t, J=7.2 Hz, 3H), 2.16(s, 3H), 3.00(t,J=6.6 Hz, 2H), 3.84-4.07(m, 4H), 3.91(s, 3H), 3.93(s, 3H), 6.73(s, 1H),7.36-7.61(m, 4H), 8.05(s, 1H) MS: 460.1[M + H]⁺ HPLC retention time[min]: 5.52(method B) 10

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.92(t, J=7.0 Hz, 3H), 2.13(s, 3H),2.95(t, J=6.2 Hz, 2H), 3.73(s, 3H), 3.79(s, 3H), 3.88-4.06(m, 4H),6.94(s, 1H), 7.11(d, J=8.5 Hz, 1H), 7.36(dd, J=8.5 Hz, J=2.3 Hz, 1H),7.64(d, J=2.1 Hz, 1H), 7.72(s, 1H), # 10.81(bs, 1H) MS: 453.3[M + H]⁺HPLC retention time [min]: 5(method C) 11

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.92(t, J=7.1 Hz, 3H), 2.12(s, 3H),2.13(s, 3H), 2.95(t, J=6.2 Hz, 2H), 3.71(s, 3H), 3.78(s, 3H),3.85-4.06(m, 4H), 6.50(d, J=7.5 Hz, 1H), 6.60(s, 1H), 6.94(s, 1H),7.00(d, J=7.7 Hz, 1H), 7.57(s, 1H), # 9.13(s, 1H) MS: 422.0[M + H]⁺ HPLCretention time [min]: 4.32(method D) 12

MS: 422.1[M + H]⁺ HPLC retention time [min]: 5.01(method B) 13

¹H-NMR(200 MHz, DMSO-d₆): δ = 2.04(s, 3H), 2.93(t, 2H), 3.46(s, 3H),3.58(s, 3H), 3.72(s, 3H), 3.78(s, 3H), 3.91(t, 2H), 6.29-6.41(m, 1H),6.38(s, 1H), 6.83(d, 1H), 6.93(s, 1H), 7.62(s, 1H), 9.31(br s, 1H)Melting point [° C.]: 252-254 14

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.92(t, J=7.2 Hz, 3H), 2.13(s, 3H),2.86-3.00(m, 2H), 3.72(s, 3H), 3.73(s, 3H), 3.78(s, 3H), 3.85-4.07(m,4H), 6.57(dd, J=8.0 Hz, J=1.8 Hz, 1H), 6.70(d, J=1.7 Hz, 1H), 6.75(d,J=8.1 Hz, 1H), 6.94(s, 1H), # 7.60(s, 1H), 8.83(s, 1H) MS: 438.2[M + H]⁺HPLC retention time [min]: 4.01(method A) 15

¹H-NMR(300 MHz, DMSO-d₆): δ = 2.17(s, 3H), 2.94(t, 2H), 3.56(s, 3H),3.69(s, 3H), 3.72(s, 3H), 3.79(s, 3H), 3.92(t, 2H), 6.23-6.31(m, 2H),6.94(s, 1H), 7.44(s, 1H), 9.06(s, 1H) Melting point [° C.]: 215-216 16

MS: 438.2[M + H]⁺ HPLC retention time [min.]: 5.53(method C) 17

MS: 444.2[M + H]⁺ HPLC retention time [min.]: 4.91(method A) 18

¹H-NMR(300 MHz, DMSO-d₆): δ = 2.16(s, 3H), 2.96(t, 2H), 3.49(s, 3H),3.74(s, 3H), 3.80(s, 3H), 3.96(t, 2H), 6.96(s, 1H), 7.45-7.52(m, 2H),7.58-7.64(m, 2H), 7.62(s, 1H) Melting point [° C.]: 140-141 19

¹H-NMR(200 MHz, DMSO-d₆): δ = 2.13(s, 3H), 2.16(s, 6H), 2.99(t, 2H),3.50(s, 3H), 3.73(s, 3H), 3.82(s, 3H), 3.90(t, 2H), 6.70(s, 2H), 6.95(d,1H), 7.43(d, 1H), 8.09(s, 1H) Melting point [° C.]: 196-198 20

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.95(t, 3H), 2.12(s, 3H), 2.99(t, 2H),3.78(s, 3H), 3.87(s, 3H), 3.94(t, 2H), 3.99(q, 2H), 6.80-6.85(m, 1H),6.89-6.92(m, 1H), 7.07-7.16(m, 2H), 7.20(s, 1H), 7.38(d, 2H) Meltingpoint [° C.]: 182-183 21

MS: 518.2[M + H]⁺ HPLC retention time [min.]: 4.45(method D) 22

¹H-NMR(200 MHz, DMSO-d₆): δ = 2.12(s, 6H), 2.99(t, 2H), 3.50(s, 3H),3.73(s, 3H), 3.82(s, 3H), 3.90(t, 2H), 6.69- 6.82(m, 2H), 6.85(s, 1H),6.95(d, 1H), 7.44(d, 1H), 9.15(s, 1H) Melting point [° C.]: 183-185 23

MS: 496.1[M + H]⁺ HPLC retention time [min.]: 5.39(method A) 24

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.90(t, J=7.1 Hz, 3H), 2.12(s, 3H),2.95(t, J=6.2 Hz, 2H), 3.73(s, 3H), 3.79(s, 3H), 3.86-4.08(m, 4H),6.95(s, 1H), 7.09-7.26(m, 1H), 7.30-7.47(m, 2H), 7.75(s, 1H) MS:444.2[M + H]⁺ HPLC retention time [min.]: 5.03(method A) 25

¹H-NMR(200 MHz, DMSO-d₆): δ = 2.14(s, 3H), 2.16(s, 6H), 3.07(t, 2H),3.53(s, 3H), 3.98(t, 2H), 6.71(s, 2H), 7.24(d, 1H), 7.35(br s, 1H),7.75(d, 1H), 8.13(s, 1H) Melting point [° C.]: 167-169 26

¹H-NMR(300 MHz, CDCl₃): δ = 0.91(t, J=7.2 Hz, 3H), 2.14(s, 3H), 3.00(t,J=6.6 Hz, 2H), 3.84-3.97(m, 2H), 3.91(s, 3H), 3.92(s, 3H), 4.03(q, J=7.0Hz, 2H), 6.73(s, 1H), 7.42-7.52(m, 2H), 7.53-7.60(m, 2H), 8.02(m, 1H)MS: 417[M + H]⁺, 434[M + NH₄]⁺ HPLC retention time [min.]: 4.87(methodB) 27

¹H-NMR(200 MHz, CDCl₃): δ = 0.92(t, 3H), 1.48(t, 3H), 2.16(s, 3H),2.98(t, 2H), 3.90(s, 3H), 3.93(t, 2H), 4.04(q, 2H), 4.16(q, 2H), 6.72(s,1H), 7.10-7.17(m, 1H), 7.21-7.30(m, 1H), 7.98(m, 1H) Melting point [°C.]: 137-138 28

¹H-NMR(400 MHz, CDCl₃): δ = 0.92(t, J=7.1 Hz, 3H), 2.16(s, 3H), 2.99(t,J=6.5 Hz, 2H), 3.86-3.96(m, 2H), 3.91(s, 3H), 3.92(s, 3H), 4.04(q, J=7.1Hz, 2H), 6.7(s, 1H), 7.09-7.16(m, 1H), 7.21-7.31(m, 3H), 8.01(s, 1H) MS:426.2[M + H]⁺, 443.1[M + NH₄]⁺ HPLC retention time [min.]: 5.47(methodB) 29

Melting point [° C.]: 142-143 30

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.70(t, J=7.1 Hz, 3H), 1.95(s, 3H),2.01(s, 3H), 2.97(t, J=6.4 Hz, 2H), 3.61-4.12(m, 4H), 3.72(s, 3H),3.79(s, 3H), 6.88-7.29(m, 4H), 6.95(s, 1H), 7.89(s, 1H) MS: 406.3[M +H]⁺, 423.3[M + NH₄]⁺ HPLC retention time [min.]: 5.4(method B) 31

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.80(t, 7.2 Hz, 3H), 2.04(s, 3H),2.89-3.05(m, 2H), 3.68-4.07(m, 4H), 3.74(s, 3H), 3.80(s, 3H), 6.96(s,1H), 7.35(d, J=2.4 Hz, 1H), 7.81(d, J=2.5 Hz, 1H), 8.03(s, 1H) MS:496.1[M + H]⁺ HPLC retention time [min.]: 5.39 (method A) 32

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.92(t, J=7.1 Hz, 3H), 2.16(s, 3H),2.95(t, J=6.2 Hz, 2H), 3.73(s, 9H), 3.79(s, 3H), 3.85-4.08(m, 4H),6.26-6.34(m, 2H), 6.37-6.43(m, 1H), 6.94(s, 1H), 7.63(s, 1H) MS:452.0[M + H]⁺ HPLC retention time [min.]: 4.94(method B) 33

MS: 496.1[M + H]⁺ HPLC retention time [min.]: 5.12(method A) 34

Melting point [° C.]: 127-129 35

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.93(t, J=7.2 Hz, 3H), 2.12(s, 3H),2.95(t, J=6.4 Hz, 2H), 3.72(s, 3H), 3.79(s, 3H), 3.87(s, 3H), 3.93(t,J=6.4 Hz, 2H), 3.99(q, J=7.2 Hz, 2H), 6.94(s, 1H), 7.06-7.21(m, 3H),7.68(s, 1H) MS: 456.2[M + H]⁺ HPLC retention time [min.]: 4.79(method A)36

MS: 474.4[M + H]⁺, 491.2[M + NH₄]⁺ HPLC retention time [min.]:5.7(method B) 37

¹H-NMR(200 MHz, CDCl₃): δ = 0.94(t, J=7.2 Hz, 3H), 2.15(s, 3H),3.68-4.12(m, 2H), 3.74(s, 3H), 3.83(s, 3H), 3.90(s, 3H), 3.91(s, 3H),3.94(s, 3H), 6.58(s, 1H), 6.70(s, 1H), 6.75(s, 1H), 8.00(s, 1H) MS:482.1[M + H]⁺ HPLC retention time [min.]: 4.5(method B) 38

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.20(t, J=7.2 Hz, 3H), 2.00(s, 3H),3.03(t, J=6.2 Hz, 2H), 3.56(q, J=7.2 Hz, 2H), 3.73(s, 3H), 3.81(s, 3H),4.04(t, J=6.3 Hz, 2H), 6.99(s, 1H), 7.46(d, J=6.9 Hz, 1H), 7.56(t, J=7.7Hz, 1H), 7.75(t, J=7.2 Hz, 1H), 7.90-8.13(m, 4H) MS: 510.2[M + H]⁺, #527.1[M + NH₄]⁺ HPLC retention time [min.]: 4.49(method B) 39

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.24(t, J=7.1 Hz, 3H), 1.99(s, 3H),2.84(s, 6H), 3.01(t, J=6.3 Hz, 2H), 3.47-3.66(m, 2H), 3.72(s, 3H),3.81(s, 3H), 4.01(t, J=6.3 Hz, 2H), 6.97(s, 1H), 7.12(d, J=7.7 Hz, 1H),7.19(d, J=7.6 Hz, 1H), 7.31-7.51(m, 2H), 7.60(d, J=8.3 Hz, 1H), 7.92(s,1H), # 8.18(d, J=7.8 Hz, 1H) MS: 485.0[M + H]⁺ HPLC retention time[min.]: 4.36(method B) 40

MS: 460.2[M + H]⁺, 477.3[M + NH₄]⁺ HPLC retention time [min.]:5.94(method B) 41

MS: 460.3[M + H]⁺ HPLC retention time [min.]: 5.03(method D) 42

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.36(t, J=7.1 Hz, 3H), 1.86(s, 3H),3.02(t, J=6.1 Hz, 2H), 3.52-3.86(m, 2H), 3.72(s, 3H), 3.77(s, 3H),3.81(s, 3H), 4.01(t, J=6.2 Hz, 2H), 6.97(s, 1H), 7.21-7.37(m, 2H),7.38-7.52(m, 2H), 7.78-7.99(m, 2H) MS: 472.2[M + H]⁺ HPLC retention time[min.]: 3.6(method B) 43

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.91(t, 3H), 2.12(s, 3H), 2.95(t, 2H),3.72(s, 3H), 3.79(s, 3H), 3.85(s, 3H), 3.93(t, 2H), 4.98(q, 2H),6.88-7.04(m, 3H), 7.14(t, 1H), 7.67(s, 1H) Melting point [° C.]: 144-14544

¹H-NMR(200 MHz, CDCl₃): δ = 0.97(t, J=7.1 Hz, 3H), 2.16(s, 3H), 2.99(t,J=6.4 Hz, 2H), 3.81-3.99(m, 2H), 3.91(s, 3H), 3.92(s, 3H), 4.07(q, J=7.1Hz, 2H), 6.72(s, 1H), 7.09(dd, J=8.2 Hz, J=2.0 Hz, 1H), 7.37(d, J=2.0Hz, 1H), 7.42(d, J=8.2 Hz, 1H), 7.98(s, 1H) MS: 460.0[M + H]⁺, #477.2[M + NH₄]⁺ HPLC retention time [min.]: 5.79(method B) 45

MS: 426.3[M + H]⁺ HPLC retention time [min.]: 4.93(method D) 46

¹H-NMR(300 MHz, DMSO-d₆): δ = 0.93(t, 3H), 2.17(s, 3H), 2.99(t, 2H),3.68(s, 3H), 3.75(s, 6H), 3.78(s, 3H), 3.94(t, 2H), 4.00(q, 2H), 6.45(s,2H), 6.80-6.85(m, 1H), 6.89-6.92(m, 1H), 7.80(d, 1H) Melting point [°C.]: 141-142 47

¹H-NMR(200 MHz, CDCl₃): δ = 0.92(t, 3H), 1.48(t, 3H), 2.17(s, 3H),2.98(t, 2H), 3.91(s, 3H), 3.93(t, 2H), 4.04(q, 2H), 4.13(q, 2H), 6.72(s,1H), 6.89-7.06(m, 3H), 7.22-7.30(m, 1H), 7.97(m, 1H) Melting point [°C.]: 131-132 48

MS: 406.3[M + H]⁺ HPLC retention time [min.]: 5.03(method D) 49

MS: 424.1[M + H]⁺, 441[M + NH₄]⁺ HPLC retention time [min.]: 5.3(methodB) Melting point [° C.]: 143-144 50

Melting point [° C.]: 157-159 51

¹H-NMR(200 MHz, CDCl₃): δ = 0.93(t, J=7.1 Hz, 3H), 2.14(s, 3H), 2.98(t,J=5.8 Hz, 2H), 3.70-4.11(m, 4H), 3.74(s, 3H), 3.85(s, 3H), 3.90(s, 3H),3.91(s, 3H), 6.42-6.58(m, 2H), 6.69(s, 1H), 7.07(d, J=8.8 Hz, 1H), #8.01(s, 1H) MS: 452.0[M + H]⁺ HPLC retention time [min.]: 4.82(method B)52

MS: 452[M + H]⁺ HPLC retention time [min.]: 4.37(method D) 53

MS: 496.1[M + H]⁺ HPLC retention time [min.]: 5.29(method A) 54

Melting point [° C.]: 135-137 55

Melting point [° C.]: 162-164 56

¹H-NMR(400 MHz, CDCl₃): δ = 0.92(t, J=7.2 Hz, 3H), 2.21(s, 3H), 2.99(t,J=6.5 Hz, 2H), 3.85(s, 6H), 3.86-3.98(m, 2H), 3.88(s, 3H), 3.90(s, 3H),3.92(s, 3H), 4.04(q, J=7.2 Hz, 2H), 6.49(s, 2H), 6.72(s, 1H), # 7.95(s,1H) MS: 482.4[M + H]⁺ HPLC retention time [min.]: 4.43(method D) 57

MS: 420.3[M + H]⁺ HPLC retention time [min.]: 5.24(method D) 58

MS: 453.3[M + H]⁺ HPLC retention time [min.]: 4.6(method A) 59

¹H-NMR(200 MHz, DMSO-d₆): δ = 0.99(t, 3H), 2.21(s, 3H), 2.96(t, 2H),3.66(s, 3H), 3.68(s, 3H), 3.75(s, 6H), 3.89(t, 2H), 4.00(q, 2H), 6.48(s,2H), 6.93(d, 2H), 7.18(t, 1H) Melting point [° C.]: 155-157 60

¹H-NMR(300 MHz, CDCl₃): δ = 1.08(t, 3H), 2.21(s, 3H), 3.02(t, 2H),3.77(s, 3H), 3.84(s, 3H), 3.88(t, 2H), 4.11(q, 2H), 6.40-6.45(m, 2H),7.50(t, 1H), 7.66-7.71(m, 1H), 8.08-8.13(m, 1H), 8.19-8.22(m, 1H)Melting point [° C.]: 179-180 61

HPLC retention time [min.]: 5.18(method E) 62

Melting point [° C.]: 187-188 63

MS: 442.0[M + H]⁺ HPLC retention time [min.]: 5.52(method B) 64

¹H NMR(300 MHz, DMSO-d₆): δ = 0.89(t, J=7.0 Hz, 3H), 2.14(s, 3H),2.31(s, 3H), 2.95(t, J=6.4 Hz, 2H), 3.72(s, 3H), 3.74(s, 3H), 3.79(s,3H), 3.88-4.01(m, 4H), 5.04(s, 2H), 6.66(dd, J=8.1 Hz, J=2.1 Hz, 1H),6.76(d, J=1.9 Hz, 1H), # 6.94(s, 1H), 7.00(d, J=8.3 Hz, 1H), 7.20(d,J=8.0 Hz, 2H), 7.34(d, J=8.0 Hz, 2H), 7.63(s, 1H) MS: 542.3[M + H]⁺ HPLCretention time [min.]: 5.09(method A) 65

MS: 558.3[M + H]⁺ HPLC retention time [min.]: 4.85(method A) 66

MS: 518.2[M + H]⁺ HPLC retention time [min.]: 5.4(method A) 67

MS: 484.3[M + H]⁺ HPLC retention time [min.]: 5.3(method D) 68

MS: 438.3[M + H]⁺ HPLC retention time [min.]: 4.98(method D) 69

MS: 556.3[M + H]⁺ HPLC retention time [min.]: 5.37(method A) 70

¹H NMR(300 MHz, DMSO-d₆): δ = 0.19(t, J=7.0 Hz, 3H), 2.20-2.40(m, 2H),2.44-2.66(m, 1H), 2.69-2.83(m, 1H), 3.02(t, J=6.2 Hz, 2H), 3.39(s, 3H),3.44-3.60(m, 2H), 3.72(s, 3H), # 3.81(s, 3H), 3.96-4.16(m, 2H), 6.99(s,1H), 7.26- 7.62(m, 5H), 7.83-7.96(m, 3H) MS: 514.4[M + H]⁺, 531.4[M +NH₄]⁺ HPLC retention time [min.]: 5.22(method B) 71

¹H NMR(200 MHz, DMSO-d₆): δ = 0.87(t, J=7.1 Hz, 3H), 2.11(s, 3H),2.31(s, 3H), 2.87-3.04(m, 2H), 3.71(s, 3H), 3.79(s, 3H), 3.84-4.04(m,4H), 5.06(s, 2H), 6.90-7.12(m, 5H), # 7.20(d, J=7.7 Hz, 2H), 7.35(d,J=7.8 Hz, 2H), 7.63(s, 1H) MS: 512.3[M + H]⁺ HPLC retention time [min.]:5.28(method A) 72

MS: 514.2[M + H]⁺ HPLC retention time [min.]: 5.17(method A) 73

MS: 514.4[M + H]⁺, 528.3[M + NH₄]⁺ HPLC retention time [min.]:5.04(method D) 74

MS: 498.3[M + H]⁺ HPLC retention time [min.]: 5.23(method D) 75

MS: 509.3[M + H]⁺ HPLC retention time [min.]: 5.25(method D) 76

Melting point [° C.]: 170-171 77

MS: 604.3[M + H]⁺ HPLC retention time [min.]: 5.29(method A) 78

Melting point [° C.]: 136-137 79

Melting point [° C.]: 170 80

MS: 476.2[M + H]⁺ HPLC retention time [min.]: 5.12(method A) 81

MS: 543.3[M + H]⁺ HPLC retention time [min.]: 4.99(method A) 82

Melting point [° C.]: 128-129 83

MS: 512.3[M + H]⁺ HPLC retention time [min.]: 5.18(method A) 84

Melting point [° C.]: 178-179 85

MS: 498.3[M + H]⁺ HPLC retention time [min.]: 5.03(method A) 86

MS: 470.3[M + H]⁺ HPLC retention time [min.]: 4.76(method D) 87

MS: 498.3[M + H]⁺ HPLC retention time [min.]: 5.23(method D) 88

¹H NMR(200 MHz, DMSO-d₆): δ = 0.14(t, J=7.2 Hz, 3H), 2.05(s, 3H),3.04(t, J=6.3 Hz, 2H), 3.54(q, J=7.1 Hz, 2H), 3.74(s, 3H), 3.82(s, 3H),4.05(t, J=6.3 Hz, 2H), 6.99(s, 1H), 7.43-7.79(m, 6H), 7.88-8.07(m, 2H),8.73-8.99(m, 2H) MS: 492.4[M + H]⁺, # 511.0[M + NH₄]⁺ HPLC retentiontime [min.]: 5.86(method B) 89

90

MS: 450.3[M + H]⁺ HPLC retention time [min.]: 4.57(method D)

Example 91 Ethyl8,9dimethoxy-3-methyl-2-(3-pyrrolidinyl-phenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylate

Following the procedure described in Example 1, ethyl(6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene)-ethanoate (ExampleIII.1), 3-nitro-benzaldehyde, and nitroethane were reacted to give ethyl8,9-dimethoxy-3-methyl-2-(3-nitrophenyl)-5,6-dihydro-pyrrolo[2,1-a]-isoquinoline-1-carboxylate.

4.5 g (10.31 mmol) of this compound were dissolved in 500 mL of warmmethanol, 2.03 g of 10% strength palladium on charcoal were added, andthe compound was hydrogenated at atmospheric pressure. The reactionmixture was filtered through a filter aid, the filtrate was evaporatedunder reduced pressure to a volume of approx. 150 mL, and the resultingprecipitate was filtered off to give 3.36 g (80.2%) of ethyl2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]-isoquinoline-1-carboxylate.

168.5 mg (1.11 mmol) of DBU and 79.9 mg (0.37 mmol) of 1,4-dibromobutanewere added to a solution of 150 mg (0.37 mmol) of ethyl2-(3-aminophenyl)-8,9-dimethoxy-3-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylateobtained as described above in 3 mL of DMF. The mixture was stirred at120° C. for 20 hours, the solvent was evaporated under reduced pressure,and the residue was taken up in an ethyl acetate/water mixture. Thelayers were separated, the aqueous layer was extracted with ethylacetate, and the combined organic phases were washed with water, driedover Na₂SO₄ and the solvent was evaporated under reduced pressure.Chromatography on a short silica gel column using adichloromethane/ethyl acetate 10:1 mixture as eluant, followed bycrystallization from diethyl ether gave the title compound.

¹H-NMR (200 MHz, CDCl₃):

δ=0.94 (t, 3H), 1.93-2.09 (m, 4H), 2.22 (s, 3H), 2.99 (t, 2H), 3.23-3.39(m, 4H), 3.90 (s, 3H), 3.91 (s, 3H), 3.93 (t, 2H), 4.05 (q, 2H),6.43-6.64 (m, 3H), 6.71 (s, 1H), 7.15-7.24 (m, 1H), 7.90 (s, 1H).

Melting point [° C.]: 141-142

1. A compound of the formula (I)

wherein x and y independently from each other denote zero or 1 with theproviso that x+y=1 or 2; R¹ and R² independently from each other denotehydrogen, C₁₋₄-alkyl or CF₃ or R¹ and R² together form a C₁₋₄-alkylenebridge; R³ and R⁴ independently from each other denote C₁₋₄-alkyl; R⁵denotes C₆₋₁₄-aryl, optionally having 1 to 3 further substituentsselected from the group consisting of halogen; C₁₋₆-alkyl which can befurther substituted with one or more radicals selected from the groupconsisting of OH, halogen, NH₂ and C₁₋₆-alkoxy; C₁₋₆alkoxy which can befurther substituted with one or more radicals selected from the groupconsisting of OH, halogen, NH₂, C₁₋₆-alkoxy and C₆₋₁₀-aryloxy; OH; NO₂;CN; CF₃; OCF₃; NR⁶R⁷; SR⁸; —O—(CH₂)₁₋₄—O— wherein the oxygen atoms arebound to the aryl moiety in ortho-position to each other; phenyloxy orbenzyloxy wherein the phenyl moieties optionally contain one furthersubstituent selected from the group consisting of C₁₋₆-alkyl,C₁₋₆-alkoxy, halogen, and NO₂; phenyl, optionally substituted with CN;and 4- to 9-membered heterocyclyl containing 1 to 4 hetero atomsselected from the group consisting of N, O, and S; R⁶ and R⁷independently from each other denote hydrogen, C₁₋₆-alkyl or, togetherwith the nitrogen atom to which they are attached, form a 5- to7-membered saturated, partially unsaturated or aromatic ring which cancontain up to 3 further hetero atoms selected from the group consistingof N, O, and S, and which ring can contain 1 to 3 substituents selectedfrom the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, C₆₋₁₀-aryl and 4to 9-membered aromatic heterocyclyl containing 1 to 4 hetero atomsselected from the group consisting of N, O, and S; and R⁸ denoteshydrogen, C₁₋₆-alkyl or C₆₋₁₀-aryl-C₁₋₆-alkyl with the proviso that8,9-dimethoxy-3-methyl-2-phenyl-5,6-dihydro-pyrrolo-[2.1-a]isoquinoline-1-carboxylicacid ethyl ester is excluded, or an isomer, a pharmaceuticallyacceptable salt, a hydrate or a hydrate of a pharmaceutically acceptablesalt thereof.
 2. A compound of formula (I) according to claim 1, whereinx and y independently from each other denote zero or 1 with the provisothat x+y=1 or 2; R¹ and R² independently from each other denotehydrogen, C₁₋₄-alkyl or CF₃ or R¹ and R² together form a C₁₋₄-alkylenebridge; R³ and R⁴ independently from each other denote C₁₋₄-alkyl; R⁵denotes (i) phenyl, optionally having 1 to 3 further substituentsselected from the group consisting of F, Cl, Br; C₁₋₆-alkyl;C₁₋₆-alkoxy; C₆₋₁₀-aryloxy-C₁₋₆-alkoxy; OH; NO₂; CN; CF₃; OCF₃; NR⁶R⁷;SR⁸; —O—(CH₂)₂₋₃—O— wherein the oxygen atoms are bound to the phenylmoiety in ortho-position to each other; phenyloxy or benzyloxy whereinthe phenyl moieties optionally contain one further substituent selectedfrom the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, F, Cl, Br, andNO₂; phenyl, optionally substituted with CN; and benzoxazolyl; (ii)napthyl, optionally having 1 to 3 further substituents selected from thegroup consisting of F, Cl, Br; C₁₋₆-alkyl; C₁₋₆-alkoxy; CF₃; and NR⁶R⁷(wherein R⁶ and R⁷ are as defined above); or (iii) phenanthrenyl; R⁶ andR⁷ independently from each other denote hydrogen, C₁₋₆-alkyl or,together with the nitrogen atom to which they are attached, form a 5- to7-membered saturated heterocyclyl which can contain up to 3 furtherhetero atoms selected from the group consisting of N, O, and S, andwhich saturated heterocyclyl can contain 1 to 3 substituents selectedfrom the group consisting of C₁₋₆-alkyl, C₁₋₆-alkoxy, C₆₋₁₀-aryl and 4-to 9-membered aromatic heterocyclyl containing 1 to 4 hetero atomsselected from the group consisting of N, O, and S; and R⁸ denoteshydrogen, C₁₋₆-alkyl or C₆₋₁₀-aryl-C₁₋₆-alkyl with the proviso that8,9-dimethoxy-3-methyl-2-phenyl-5,6-dihydro-pyrrolo-[2.1-a]isoquinoline-1-carboxylicacid ethyl ester is excluded, or an isomer, a pharmaceuticallyacceptable salt, a hydrate or a hydrate of a pharmaceutically acceptablesalt thereof.
 3. A compound of formula (I) according to claim 1, whereinx and y independently from each other denote zero or 1 with the provisothat x+y=1 or 2; R¹ and R² independently from each other denotehydrogen, C₁₋₄-alkyl or CF₃ or R^(1 and R) ² together form a methylenebridge; R³ and R⁴ independently from each other denote C₁₋₄-alkyl; R⁵denotes (i) phenyl, optionally having 1 to 3 further substituentsselected from the group consisting of F, Cl, Br; CH₃, C₂H₅, i-C₃H₇;OCH₃, OC₂H₅, i-OC₃H₇; phenyloxy-C₁₋₄-alkoxy; OH; NO₂; CN; CF₃; OCF₃;NR⁶R⁷; SR⁸; —O—(CH₂)₂₋₃—O— wherein the oxygen atoms are bound to thephenyl moiety in ortho-position to each other; phenyloxy or benzyloxywherein the phenyl moieties optionally contain one further substituentselected from the group consisting of C₁₋₄-alkyl, C₁₋₄-alkoxy, F, Cl,Br, and NO₂; phenyl, optionally substituted with CN; and benzoxazolyl;(ii) napthyl, optionally having 1 to 3 further substituents selectedfrom the group consisting of F, Cl, Br; C₁₋₄-alkoxy; CF₃; and NR⁶R⁷(wherein R⁶ and R⁷ are as defined above); or (iii) phenanthrenyl; R⁶ andR⁷ independently from each other denote hydrogen, C₁₋₆-alkyl or,together with the nitrogen atom to which they are attached, form a 5- to7-membered saturated ring; and R⁸ denotes hydrogen, C₁₋₄-alkyl orphenyl-C₁₋₄-alkyl with the proviso that8,9-dimethoxy-3-methyl-2-phenyl-5,6-dihydro-pyrrolo-[2.1-a]isoquinoline-1-carboxylicacid ethyl ester is excluded, an isomer, pharmaceutically acceptablesalt, a hydrate or a hydrate of a pharmaceutically acceptable saltthereof.
 4. A process for manufacturing a compound according to claim 1comprising the reaction of a compound of the formula

wherein x, y, R¹, R² and R⁴ are as defined in claim 1, (A) withcompounds of the formulae

wherein R³ and R⁵ are as defined in claim 1, or (B) with a compound ofthe formula

wherein R³ and R⁵ are as defined in claim 1, and optionally (C) theconversion of compound (I) obtained through either process [A] or [B]into an isomer, a (pharmaceutically acceptable) salt, a hydrate or ahydrate of a (pharmaceutically acceptable) salt thereof.
 5. Method ofmanufacturing a pharmaceutical composition by combining one or more ofthe compounds according to claims 1 to 3 with one or morepharmacologically acceptable formulating agent.
 6. Pharmaceuticalcomposition comprising as an active ingredient an effective amount ofone or more of the compounds according to claims 1 to 3 and one or morepharmacologically acceptable formulating agent.
 7. A pharmaceuticalcomposition in dosage unit form comprising an effective amount of acompound according to claims 1 to 3 together with an inertpharmaceutical carrier.
 8. A method of treating breast cancer in amammals comprising administering to said mammal an effective amount ofone or more compound according to claims 1 to 3 either alone or inadmixture with a diluent or in the form of a pharmaceutical composition.